Benzimidazole derivatives and their use for modulating the GABAA receptor complex

ABSTRACT

This invention relates to novel benzimidazole derivatives of formula (I), pharmaceutical compositions containing these compounds, and methods of treatment therewith. The compounds of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABA A  receptor complex, and in particular for combating anxiety and related diseases

TECHNICAL FIELD

This invention relates to novel benzimidazole derivatives,pharmaceutical compositions containing these compounds, and methods oftreatment therewith.

The compounds of the invention are useful in the treatment of centralnervous system diseases and disorders, which are responsive tomodulation of the GABA_(A) receptor complex, and in particular forcombating anxiety and related diseases.

BACKGROUND ART

The modulatory sites on the GABA_(A) receptor complex, such as forexample the benzodiazepine receptor, are the targets for anxiolyticdrugs, such as the classical anxiolytic benzodiazepines.

Multiple isoforms of the GABA_(A) receptor exist; each receptor is apentameric complex comprising subunits drawn from α₁₋₆, β₁₋₃, γ₁₋₃, δ,ε, and θ subunit isoforms. The classical anxiolytic benzodiazepines showno subtype selectivity. It has been suggested that one of the keyelements in the disadvantages of the classical benzodiazepanes (such assedation, dependency, and cognitive impairment) is relates to the α1subunit of the GABA_(A) receptors. Thus compounds with selectivity forthe α2 and/or α3 subunits over the α1 subunit are expected to have animproved side effect profile.

EP 616807 describes benzimidazole compounds for use as benzodiazepinereceptor ligands.

WO 96/33194, WO 96/33191 and WO 96/33192 describe benzimidazolecompounds having affinity for the GABA receptor complex.

WO 98/34923 describes phenylbenzimidazole derivatives as ligands for theGABA receptor complex.

WO 98/17651 and WO 00/78728 describe benzimidazole compounds for use ase.g. anaesthetics.

However, there is a continued strong need to find compounds with anoptimized pharmacological profile. Furthermore, there is a strong needto find effective compounds without unwanted side effects associatedwith older compounds.

SUMMARY OF THE INVENTION

In its first aspect, the invention provides a compound of the Formula I:

or an N-oxide thereof, or any of its isomers or any mixture of itsisomers, or a pharmaceutically acceptable salt thereof,wherein R and R′ are defined as below.

In its second aspect, the invention provides a pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundof the invention, or an N-oxide thereof, or any of its isomers or anymixture of its isomers, or a pharmaceutically acceptable salt thereof,together with at least one pharmaceutically acceptable carrier,excipient or diluent.

In a further aspect, the invention provides the use of a compound of theinvention, or an N-oxide thereof, or any of its isomers or any mixtureof its isomers, or a pharmaceutically acceptable salt thereof, for themanufacture of a pharmaceutical composition for the treatment,prevention or alleviation of a disease or a disorder or a condition of amammal, including a human, which disease, disorder or condition isresponsive to modulation of the GABA_(A) receptor complex in the centralnervous system.

In a still further aspect, the invention relates to a method fortreatment, prevention or alleviation of a disease or a disorder or acondition of a living animal body, including a human, which disorder,disease or condition is responsive to modulation of the GABA_(A)receptor complex in the central nervous system, which method comprisesthe step of administering to such a living animal body in need thereof atherapeutically effective amount of a compound of the invention, or anN-oxide thereof, or any of its isomers or any mixture of its isomers, ora pharmaceutically acceptable salt thereof.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

Substituted Benzimidazole Derivatives

In its first aspect the present invention provides a compound of generalformula (I):

or an N-oxide thereof, or any of its isomers or any mixture of itsisomers,or a pharmaceutically acceptable salt thereof,wherein

-   R represents cycloalkyl; and-   R′ represents a 5-7-membered heterocyclic ring;    -   which heterocyclic ring may optionally be substituted one or        more substituents independently selected from the group        consisting of with halo, hydroxy, amino, alkylamino, aminoalkyl,        alkylaminoalkyl, cyano, nitro, trifluoromethyl,        trifluoromethoxy, alkoxy, alkoxyalkyl, cycloalkoxy, alkyl,        cycloalkyl, cycloalkylalkyl, alkenyl, and alkynyl.

In one embodiment, R represents cyclopropyl or cyclohexyl. In a secondembodiment, R represents cyclopropyl. In a third embodiment, Rrepresents cyclohexyl.

In a second embodiment, R′ represents a 5-7-membered heterocyclic ring;which heterocyclic ring may optionally be substituted one or moresubstituents independently selected from the group consisting of withhalo, hydroxy, amino, alkylamino, aminoalkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, alkoxy, cycloalkoxy, alkyl,cycloalkyl, cycloalkylalkyl, alkenyl, and alkynyl

In a further embodiment, R′ represents a heterocyclic ring selected fromthe group of pyridyl, thiazolyl, isoxazolyl, imidazolyl, pyrrolyl andpyrazolyl, which heterocyclic ring may optionally be substituted withone or more halo.

In a still further embodiment, R′ represents pyridyl optionallysubstituted with one or more halo. In a special embodiment, R′represents pyridin-3-yl. In a further embodiment, R′ represents pyridylsubstituted with one halo, such as fluoro. In a special embodiment, R′represent fluoropyridyl, such as 2-fluoro-pyridin-5-yl.

In a further embodiment, R′ represents thiazolyl, such as 2-thiazolyl.

In a still further embodiment, R′ represents isoxazolyl, such as3-isoxazolyl.

In a further embodiment, R′ represents imidazolyl, such as 1-imidazolyl.

In a still further embodiment, R′ represents pyrrolyl, such as1-pyrrolyl.

In a further embodiment, R′ represents pyrazolyl, such as 1-pyrazolyl.

In a still further embodiment, the chemical compound of the invention isan N-oxide of a compound of general formula (I). In a specialembodiment, R′ represents a pyridyl-N-oxide, such as 3-pyridyl-N-oxide.

In a special embodiment the chemical compound of the invention is

-   5-Cyclopropyl-1-(3-(3-pyridyl)phenyl)benzimidazole;-   5-Cyclopropyl-1-(3-(2-thiazolyl)phenyl)benzimidazole;-   5-Cyclopropyl-1-(3-(2-fluoro-5-pyridyl)phenyl)benzimidazole;-   5-Cyclopropyl-1-(3-(3-isoxazolyl)phenyl)benzimidazole;-   5-Cyclopropyl-1-(3-(1-oxy-3-pyridyl)phenyl)benzimidazole;-   5-Cyclohexyl-1-(3-(1-imidazolyl)phenyl)benzimidazole;-   5-Cyclohexyl-1-(3-(1-pyrrolyl)phenyl)benzimidazole;-   5-Cyclohexyl-1-(3-(1-pyrazolyl)phenyl)benzimidazole;-   or an N-oxide thereof, or any of its isomers or any mixture of its    isomers,-   or a pharmaceutically acceptable salt thereof.

Any combination of two or more of the embodiments as described above isconsidered within the scope of the present invention.

Definition of Substituents

In the context of this invention halo represents fluoro, chloro, bromoor iodo.

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contain of from one to six carbon atoms (C₁₋₆-alkyl),including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl andisohexyl. In a preferred embodiment alkyl represents a C₁₋₄-alkyl group,including butyl, isobutyl, secondary butyl, and tertiary butyl. Inanother preferred embodiment of this invention alkyl represents aC₁₋₃-alkyl group, which may in particular be methyl, ethyl, propyl orisopropyl.

In the context of this invention an alkenyl group designates a carbonchain containing one or more double bonds, including di-enes, tri-enesand poly-enes. In a preferred embodiment the alkenyl group of theinvention comprises of from two to six carbon atoms (C₂₋₆-alkenyl),including at least one double bond. In a most preferred embodiment thealkenyl group of the invention is ethenyl; 1- or 2-propenyl; 1-, 2- or3-butenyl, or 1,3-butdienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or1,3-hexdienyl, or 1,3,5-hextrienyl.

In the context of this invention an alkynyl group designates a carbonchain containing one or more triple bonds, including di-ynes, tri-ynesand poly-ynes. In a preferred embodiment the alkynyl group of theinvention comprises of from two to six carbon atoms (C₂₋₄-alkynyl),including at least one triple bond. In its most preferred embodiment thealkynyl group of the invention is ethynyl; 1-, or 2-propynyl; 1-, 2-, or3-butynyl, or 1,3-butdiynyl; 1-, 2-, 3-, 4-pentynyl, or 1,3-pentdiynyl;1-, 2-, 3-, 4-, or 5-henynyl, or 1,3-hexdiynyl or 1,3,5-hextriynyl.

In the context of this invention a cycloalkyl group designates a cyclicalkyl group, preferably containing of from three to seven carbon atoms(C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

Alkoxy means O-alkyl, wherein alkyl is as defined above.

Alkoxyalkyl means alkoxy as above and alkyl as above, meaning forexample, methoxymethyl.

Cycloalkoxy means O-cycloalkyl, wherein cycloalkyl is as defined above.

Cycloalkylalkyl means cycloalkyl as above and alkyl as above, meaningfor example, cyclopropylmethyl.

In the context of this invention alkylamino designates —NH-alkyl or—N-(alkyl)₂, wherein alkyl is as defined above.

In the context of this invention a 5-7-membered heterocyclic ringdesignates a 5-7 membered monocyclic group, and which group holds one ormore heteroatoms in its ring structure. Preferred heteroatoms includenitrogen (N), oxygen (O), and sulphur (S). The ring structure may inparticular be aromatic (i.e. a heteroaryl), saturated or partiallysaturated.

Examples of preferred aromatic heterocyclic monocyclic 5-membered groupsof the invention include furan, in particular 2- or 3-furyl; thiophene,in particular 2- or 3-thienyl; pyrrole (azole), in particular 1-, 2- or3-pyrrolyl; oxazole, in particular oxazol-(2-, 4- or 5-)yl; thiazole, inparticular thiazol-(2-, 4-, or 5-)yl; imidazole, in particularimidazol-(1-, 2-, 4- or 5-)yl; pyrazole, in particular pyrazol-(1-, 3-,4- or 5-)yl; isoxazole, in particular isoxazol-(3-, 4- or 5-)yl;isothiazole, in particular isothiazol-(3-, 4- or 5-)yl;1,2,3-oxadiazole, in particular 1,2,3-oxadiazol-(4- or 5-)yl;1,2,4-oxadiazole, in particular 1,2,4-oxadiazol-(3- or 5-)yl;1,2,5-oxadiazole, in particular 1,2,5-oxadiazol-(3- or 4-)yl;1,3,4-oxadiazole, in particular 1,3,4-oxadiazol-(2- or 5-)yl;1,2,3-triazole, in particular 1,2,3-triazol-(1-, 4- or 5-)yl;1,2,4-triazole, in particular 1,2,4-triazol(1-, 3- or 4-)yl;1,2,4-thiadiazole, in particular 1,2,4-thiadiazol-(3- or 5-)yl;1,2,5-thiadiazole, in particular 1,2,5-thiadiazol-(3- or 4-)yl;1,3,4-thiadiazole, in particular 1,3,4-thiadiazol-(2- or 5-)yl; andtetrazole, in particular tetrazol-(1- or 5-)yl.

Examples of preferred saturated or partially saturated heterocyclicmonocyclic 5-membered groups of the invention include 1,3-dioxolan, inparticular 1,3-dioxolan-(2- or 4-)yl; imidazolidine, in particularimidazolidin-(1-, 2-, 3-, 4- or 5-)yl; 2-imidazoline, in particular2-imidazolin-(1-, 2-, 4- or 5-)yl; 3-imidazoline, in particular3-imidazolin-(1-, 2-, 4- or 5-)yl; 4-imidazoline, in particular4-imidazolin-(1-, 2-, 4- or 5-)yl; dihydro-oxazole (oxazoline), inparticular dihydro-oxazol-(2-, 4- or 5-)yl; tetrahydro-oxazole(oxazolidine), in particular tetrahydrooxazol-(2-, 4- or 5-)yl;1,2,3-oxadiazoline, in particular 1,2,3-oxadiazol-(4- or 5-)yl;1,2,4-oxadiazoline, in particular 1,2,4-oxadiazolin-(3- or 5-)yl;1,2,5-oxadiazoline, in particular 1,2,5-oxadiazolin-(3- or 4-)yl;1,2,3-oxadiazolidine, in particular 1,2,3-oxadiazolidin-(4- or 5-)yl;1,2,4-oxadiazolidine, in particular 1,2,4-oxadiazolidin-(3- or 5-)yl;1,2,5-oxadiazolidine, in particular 1,2,5-oxadiazolidin-(3- or 4-)yl;dihydro-pyrrole (pyrroline), in particular dihydro-pyrrol-(1-, 2- or3-)yl; tetrahydro-pyrrole (pyrrolidine), in particulartetrahydro-pyrrol-(1-, 2- or 3-)yl; pyrazolidine, in particularpyrazolidin-(1-, 2-, 3-, 4- or 5-)yl; 2-pyrazoline, in particular2-pyrazolin-(1-, 3-, 4- or 5-)yl; and 3-pyrazoline, in particular3-pyrazolin-(1-, 3-, 4- or 5-)yl.

Examples of preferred aromatic heterocyclic monocyclic 6-membered groupsof the invention include pyridine, in particular pyridin-(2-, 3- or4-)yl; pyridazine, in particular pyridazin-(3- or 4-)yl; pyrimidine, inparticular pyrimidin-(2-, 4- or 5-)yl; pyrazine, in particularpyrazin-(2-, 3-, 5- or 6-)yl; 1,3,5-triazine, in particular1,3,5-triazin-(2-, 4- or 6-)yl; and phosphinine, in particularphosphinin-(2-, 3- or 4-)yl.

Examples of preferred saturated or partially saturated heterocyclicmonocyclic 6-membered groups of the invention include 1,4-dioxolane, inparticular 1,4-dioxolan-(2- or 3-)yl; 1,4-dithiane, in particular1,4-dithian-(2- or 3-)yl; morpholine, in particular morpholin-(2-, 3- or4-)yl; 1,4-oxazine, in particular 1,4-oxazin-(2-)yl; oxadiazine, inparticular oxadiazin-(2-, 3- or 5-)yl; piperidine, in particularpiperidin-(1-, 2-, 3- or 4-)yl; piperazine, in particular piperazin-(1-,2-, 3- or 4-)yl; dihydro-pyrane, in particular dihydro-pyran-(2-, 3- or4-)yl; tetrahydro-pyrane, in particular tetrahydro-pyran-(2-, 3- or4-)yl; thiomorpholine, in particular thiomorpholin-(2-, 3- or 4-)yl; and1,3,5-trithiane, in particular 1,3,5-trithian-(2-)yl.

Examples of preferred saturated or partially saturated heterocyclicmonocyclic 7-membered groups of the invention include homopiperidine, inparticular homopiperidin-(1-, 2-, 3- or 4-)yl; and homopiperazine, inparticular homopiperazin-(1-, 2-, 3- or 4-)yl.

Pharmaceutically Acceptable Salts

The chemical compound of the invention may be provided in any formsuitable for the intended administration. Suitable forms includepharmaceutically (i.e. physiologically) acceptable salts, and pre- orprodrug forms of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride derived from hydrochloric acid, the hydrobromidederived from hydrobromic acid, the nitrate derived from nitric acid, theperchlorate derived from perchloric acid, the phosphate derived fromphosphoric acid, the sulphate derived from sulphuric acid, the formatederived from formic acid, the acetate derived from acetic acid, theaconate derived from aconitic acid, the ascorbate derived from ascorbicacid, the benzenesulphonate derived from benzensulphonic acid, thebenzoate derived from benzoic acid, the cinnamate derived from cinnamicacid, the citrate derived from citric acid, the embonate derived fromembonic acid, the enantate derived from enanthic acid, the fumaratederived from fumaric acid, the glutamate derived from glutamic acid, theglycolate derived from glycolic acid, the lactate derived from lacticacid, the maleate derived from maleic acid, the malonate derived frommalonic acid, the mandelate derived from mandelic acid, themethanesulphonate derived from methane sulphonic acid, thenaphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, thephthalate derived from phthalic acid, the salicylate derived fromsalicylic acid, the sorbate derived from sorbic acid, the stearatederived from stearic acid, the succinate derived from succinic acid, thetartrate derived from tartaric acid, the toluene-p-sulphonate derivedfrom p-toluene sulphonic acid, and the like. Such salts may be formed byprocedures well known and described in the art. Other acids such asoxalic acid, which may not be considered pharmaceutically acceptable,may be useful in the preparation of salts useful as intermediates inobtaining a chemical compound of the invention and its pharmaceuticallyacceptable acid addition salt.

Metal salts of a chemical compound of the invention include alkali metalsalts such as the sodium salt of a chemical compound of the inventioncontaining a carboxy group.

In the context of this invention the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts.Preferred “onium salts” include the alkyl-onium salts, thecycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

Examples of pre- or prodrug forms of the chemical compound of theinvention include examples of suitable prodrugs of the substancesaccording to the invention include compounds modified at one or morereactive or derivatizable groups of the parent compound. Of particularinterest are compounds modified at a carboxyl group, a hydroxyl group,or an amino group. Examples of suitable derivatives are esters oramides.

The chemical compound of the invention may be provided in dissoluble orindissoluble forms together with a pharmaceutically acceptable solventsuch as water, ethanol, and the like. Dissoluble forms may also includehydrated forms such as the monohydrate, the dihydrate, the hemihydrate,the trihydrate, the tetrahydrate, and the like. In general, thedissoluble forms are considered equivalent to indissoluble forms for thepurposes of this invention.

Steric Isomers

It will be appreciated by those skilled in the art that the compounds ofthe present invention may contain one or more chiral centres and thatsuch compounds exist in the form of isomers.

The racemates of these isomers and the individual isomers themselves arewithin the scope of the present invention.

Methods for the resolvation of optical isomers, known to those skilledin the art may be used, and will be apparent to the average workerskilled in the art. Such methods include those discussed by J. Jaques,A. Collet, and S. Wilen in “Enantiomers, Racemates, and Resolutions”,John Wiley and Sons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

N-oxides

In the context of this invention an N-oxide designates an oxidederivative of a ntrogen containing compound, e.g. N-containingheterocyclic compounds capable of forming such N-oxides, and compoundsholding one or more amino groups. For example, the N-oxide of a compoundcontaining a pyridyl may be the 1-oxy-pyridin-2, -3 or -4-yl derivative.

N-oxides of the compounds of the invention may be prepared by oxidationof the corresponding nitrogen base using a conventional oxidizing agentsuch as hydrogen peroxide in the presence of an acid such as acetic acidat an elevated temperature, or by reaction with a peracid such asperacetic acid in a suitable solvent, e.g. dichloromethane, ethylacetate or methyl acetate, or in chloroform or dichloromethane with3-chloroperoxybenzoic acid.

Labelled Compounds

The compounds of the invention may be used in their labelled orunlabelled form. In the context of this invention “label” stands for thebinding of a marker to the compound of interest that will allow easyquantitative detection of said compound.

The labelled compounds of the invention may be useful as diagnostictools, radio tracers, or monitoring agents in various diagnosticmethods, and for in vivo receptor imaging.

The labelled isomer of the invention preferably contains at least oneradionuclide as a label. Positron emitting radionuclides are allcandidates for usage. In the context of this invention the radionuclideis preferably selected from ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C,¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F.

The physical method for detecting the labelled isomer of the presentinvention may be selected from Position Emission Tomography (PET),Single Photon Imaging Computed Tomography (SPECT), Magnetic ResonanceSpectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed AxialX-ray Tomography (CAT), or combinations thereof.

Methods of Preparation

The chemical compounds of the invention may be prepared by conventionalmethods for chemical synthesis, e.g. those described in the workingexamples. The starting materials for the processes described in thepresent application are known or may readily be prepared by conventionalmethods from commercially available chemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

The compounds of this invention may exist in unsolvated as well as insolvated forms with pharmaceutically acceptable solvents such as water,ethanol and the like. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of this invention.

Biological Activity

Compounds of the invention are capable of modulating the GABA_(A)receptor complex. They may be tested for their ability to bind to theGABA_(A) receptor complex, including specific subunits thereof.

The compounds of the present invention, being ligands for thebenzodiazepine binding site on GABA_(A) receptors, are therefore of usein the treatment and/or prevention of a variety of disorders of thecentral nervous system. Thus in further aspect, the compounds of theinvention are considered useful for the treatment, prevention oralleviation of a disease, disorder or condition responsive to modulationof the GABA_(A) receptor complex in the central nervous system.

In a special embodiment, the compounds of the invention are considereduseful for the treatment, prevention or alleviation of

-   -   anxiety disorders, such as panic disorder with or without        agoraphobia, agoraphobia without history of panic disorder,        animal and other phobias including social phobias,        obsessive-compulsive disorder, and generalized or        substance-induced anxiety disorder;    -   stress disorders including post-traumatic and acute stress        disorder;    -   sleep disorders;    -   memory disorder;    -   neuroses;    -   convulsive disorders, for example epilepsy, or febrile        convulsions in children;    -   migraine;    -   depressive or bipolar disorders, for example single-episode or        recurrent major depressive disorder, dysthymic disorder, bipolar        I and bipolar II manic disorders, and cyclothymic disorder,    -   psychotic disorders, including schizophrenia;    -   neurodegeneration arising from cerebral ischemia;    -   attention deficit hyperactivity disorder;    -   pain and nociception;    -   emesis, including acute, delayed and anticipatory emesis, in        particular emesis induced by chemotherapy or radiation;    -   motion sickness, post-operative nausea and vomiting;    -   eating disorders including anorexia nervosa and bulimia nervosa;    -   premenstrual syndrome;    -   muscle spasm or spastcity, e.g. in paraplegic patients;    -   the effects of substance abuse or dependency, including alcohol        withdrawal;    -   cognitive disorders, such as Alzheimer's disease; and    -   disorders of circadian rhythm, e.g. in subjects suffering from        the effects of jet lag or shift work.

Preferably the compounds of the invention are considered useful for thetreatment, prevention or alleviation of anxiety disorders, such as panicdisorder with or without agoraphobia, agoraphobia without history ofpanic disorder, animal and other phobias including social phobias,obsessive-compulsive disorder, and generalized or substance-inducedanxiety disorder;

Further, the compounds of the invention may be useful as radioligands inassays for detecting compounds capable of binding to the human GABA_(A)receptor.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof the invention.

While a compound of the invention for use in therapy may be administeredin the form of the raw chemical compound, it is preferred to introducethe active ingredient, optionally in the form of a physiologicallyacceptable salt, in a pharmaceutical composition together with one ormore adjuvants, excipients, carriers, buffers, diluents, and/or othercustomary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising a compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers therefore, and,optionally, other therapeutic and/or prophylactic ingredients, know andused in the art. The carrier(s) must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and notharmful to the recipient thereof.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, bronchial, nasal, pulmonal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof. Such forms includesolids, and in particular tablets, filled capsules, powder and pelletforms, and liquids, in particular aqueous or non-aqueous solutions,suspensions, emulsions, elixirs, and capsules filled with the same, allfor oral use, suppositories for rectal administration, and sterileinjectable solutions for parenteral use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound of the present invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations, intended for conversionshortly before use to liquid form preparations for oral administration.Such liquid forms include solutions, suspensions, and emulsions. Inaddition to the active component such preparations may comprisecolorants, flavours, stabilisers, buffers, artificial and naturalsweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the chemical compound of theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantifies ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

A therapeutically effective dose refers to that amount of activeingredient, which ameliorates the symptoms or condition. Therapeuticefficacy and toxicity, e.g. ED₅₀ and LD₅₀, may be determined by standardpharmacological procedures in cell cultures or experimental animals. Thedose ratio between therapeutic and toxic effects is the therapeuticindex and may be expressed by the ratio LD₅₀/ED₅₀. Pharmaceuticalcompositions exhibiting large therapeutic indexes are preferred.

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired, and the exact dosage should of course be determined by thepractitioner.

The actual dosage depend on the nature and severity of the disease beingtreated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

EXAMPLES

The invention is further illustrated with reference to the followingexamples, which are not intended to be in any way limiting to the scopeof the invention as claimed.

Preparation of Intermediates

4-Fluoro-3-nitro-1-cyclopropylbenzene was prepared from2-fluoro-5-iodo-1-nitrobenzene and tricyclopropylindium according to themethod described in J. Am. Chem. Soc. 2001, 123, 4155-4160.

-   3-(3-Pyridyl)aniline was prepared as described in WO 96/33191.-   3-(2-Fluoro-5-pyridyl)aniline was prepared analogously from    3-nitrophenylboronic acid and 2-fluoro-5-bromopyridine.

-   3-Nitro-thio-benzamide. To a stirred solution of 3-nitrobenzonitril    (14.5 g, 98 mmol) and diethyl dithiophosphate (16.5 ml, 98 mmol) in    ethyl acetate (200 ml) was led gaseous hydrogen chloride. When the    evolution of heat had ceased the gas inlet was disconnected and the    resultant mixture was left with stirring at ambient temperature over    night. Saturated, aqueous sodium carbonate (400 ml) was added, and    the layers were separated. The organic layer was dried over    magnesium sulphate and concentrated under reduced pressure. The    desired product precipitated from the concentrate upon trituration    with petroleum ether to afford 17.74 g.-   2-(3-Nitrophenyl)thiazole. To a suspension of the above product    (17.74 g, 97 mmol) in glacial acetic acid (150 ml) was added    chloroacetaldehyde (12.7 ml, 100 mmol) and the resultant mixture was    stirred at 125° C. for 2 hours. The cooled mixture was poured into    ice-water and rendered alkaline by addition of aqueous sodium    hydroxide (12M). Ethyl acetate was added, and the resultant emulsion    was filtered through celite prior to separation of the layers. The    aqueous layer was extracted 3 times with ethyl acetate, and the    combined organic layers were dried over magnesium sulphate and    concentrated under reduced pressure. The concentrate was purified by    column chromatography on silica gel eluting with a mixture of ethyl    acetate and ligroin (1:1 v/v) to afford the desired product (6.6 g).-   3-(2-Thiazolyl)aniline. To a suspension of the above product (6.1 g,    29.6 mmol) in ethanol (170 ml) was added Raney nickel (0.5 g) and    the resultant mixture was hydrogenated at ambient pressure until the    hydrogen uptake had ceased. Filtration through celite and    evaporation of the solvent from the filtrate left the desired    product, quantitatively.

-   3-Nitrobenzaldehyde oxime. To a suspension of 3-nitrobenzaldehyde    (50.5 g, 0.33 mol) in abs. ethanol (500 ml) was added hydroxylamine,    hydrochloride (34.89, 0.50 mol) and triethylamine (46.5 ml, 0.33    mol) and the resultant mixture was stirred at reflux over night. The    solvent was distilled off under reduced pressure, and water was    added to the residue. The resultant solution was rendered alkaline    by addition of saturated, aqueous sodium carbonate and the    precipitate was filtered off, washed with water and is air-dried to    leave the product (51.7 g).-   3-(3-Nitrophenyl)isoxazole. To a solution of the above product (10.0    g, 60.2 mmol) in anhydrous dimethyl formamide (500 ml) was added    N-chlorosuccinimide (9.6 g, 72.3 mmol) and the resultant mixture was    stirred at 60° C. for 3 hours. The mixture was cooled in an ice-bath    and vinyl bromide (40 ml, 0.57 mol) was added dropwise. The    resultant solution was maintained at 0° C. while a solution of    triethyl amine (42 ml, 0.3 mol) in anhydrous dimethyl formamide was    added cautiously over 2 hours. After the addition the mixture was    stirred at ambient temperature over night. The solvent was distilled    off under reduced pressure and the residue was partitioned between    water and ethyl acetate. The layers were separated and the organic    layer was washed with brine, dried over sodium sulphate and    evaporated to dryness. The residue was purified by column    chromatography on silica gel using a mixture of ethyl acetate and    petroleum ether (1:9, v/v) as the eluent to leave the product (7.1    g).

-   3-(3-Aminophenyl)isoxazole. A suspension of the above product (7.1    g, 37.4 mmol) in abs. ethanol (100 ml) was hydrogenated at ambient    pressure, using Pd (5% on activated carbon) as the catalyst, until    the hydrogen uptake had ceased. The resultant mixture was filtered    through celite and the filtrate was evaporated to leave the desired    product as a yellow oil (5.75 g).

Example 1

4-Cyclopropyl-2-nitro-N-(3-(3-pyridyl)phenyl)aniline. To a solution ofN-(3-(3-pyridyl)phenyl)formamide (1.26 g, 6.4 mmol) in anhydrousdimethyl formamide (10 ml) was added sodium hydride (0.82 g 60%dispersion in mineral oil, 6.4 mmol). When the evolution of hydrogen hadceased, 4-fluoro-3-nitrocyclopropylbenzene (0.58 g, 3.2 mmol) was addedand the resultant mixture was stirred at room temperature for 2 hoursand was then poured into 4 volumes of water. Ethyl acetate was added andthe resultant mixture was filtered through celite prior to separation ofthe layers. The aqueous layer was extracted with ethyl acetate, and thecombined organic extracts were washed with aqueous calcium chloride(3M), dried over magnesium sulphate and evaporated to dryness. Theresidue was purified by column chromatography on silica gel using amixture of ethyl acetate and petroleum ether (1:1 v/v) as the eluent toafford the desired product (0.5 g).

-   4-Cyclopropyl-2-nitro-N-(3-(2-thiazolyl)phenyl)aniline was prepared    analogously from 4-fluoro-3-nitrocyclopropylbenzene and    N-(3-(2-thiazolyl)phenyl)formamide.-   4-Cyclopropyl-2-nitro-N-(3-(2-fluoro-5-pyridyl)phenyl)aniline was    prepared analogously from 4-fluoro-3-nitrocyclopropylbenzene and    N-(3-(2-fluoro-5-pyridyl)phenyl)formamide.-   4-Cyclopropyl-2-nitro-N-(3-(3-isoxazolyl)phenyl)aniline is prepared    analogously from 4-fluoro-3-nitrocyclopropylbenzene and    N-(3-(3-isoxazolyl)phenyl)formamide.

-   2-Amino-4-cyclopropyl-N-(3-(3-pyridyl)phenyl)aniline was prepared by    hydrogenation of    4-cyclopropyl-2-nitro-N-(3-(3-pyridyl)phenyl)aniline in abs.    ethanol, using Pd (5% on activated carbon) as the catalyst.-   2-Amino-4-cyclopropyl-N-(3-(2-thiazolyl)phenyl)aniline was prepared    by hydrogenation of    4-cyclopropyl-2-nitro-N-(3-(2-thiazolyl)phenyl)aniline in abs.    ethanol, using Raney nickel as the catalyst.-   2-Amino-4-cyclopropyl-N-(3-(2-fluoro-5-pyridyl)phenyl)aniline was    prepared by hydrogenation of    4-cyclopropyl-2-nitro-N-(3-(2-fluoro-5-pyridyl)phenyl)aniline in    abs. ethanol, using Pd (5% on activated carbon) as the catalyst.-   2-Amino-4-cyclopropyl-N-(3-(3-isoxazolyl)phenyl)aniline is prepared    by hydrogenation of    4-cyclopropyl-2-nitro-N-(3-(3-isoxazolyl)phenyl)aniline in abs.    ethanol, using Pd (5% on activated carbon) as the catalyst.-   5-Cyclopropyl-1-(3-(3-pyridyl)phenyl)benzimidazole. To a solution of    2-amino-4-cyclopropyl-N-(3-(3-pyridyl)phenyl)aniline (0.35 g, 1.2    mmol) in tetrahydrofurane (10 ml) was added triethyl orthoformate    (0.64 ml, 2.5 mmol) and a catalytic amount of p-toluenesulphonic    acid and the resultant mixture was stirred at reflux for 1 hour. The    solvent was removed under reduced pressure and the residue was    partitioned between water and ethyl acetate. The organic layer was    washed with saturated, aqueous sodium carbonate, dried over    magnesium sulphate and evaporated to dryness. The desired product    crystallised from the residue upon trituration with diethyl ether    (0.29 g) Mp 89-90° C.-   5-Cyclopropyl-1-(3-(2-thiazolyl)phenyl)benzimidazole was prepared in    a similar manner from    2-amino-4-cyclopropyl-N-(3-(2-thiazolyl)phenyl)aniline Mp 75-77° C.-   5-Cyclopropyl-1-(3-(2-fluoro-5-pyridyl)phenyl)benzimidazole was    prepared in a similar manner from    2-amino-4-cyclopropyl-N-(3-(2-fluoro-5-pyridyl)phenyl)aniline Mp    145-146° C.-   5-Cyclopropyl-1-(3-(3-isoxazolyl)phenyl)benzimidazole is prepared in    a similar manner from    2-amino-4-cyclopropyl-N-(3-(3-isoxazolyl)phenyl)aniline.

Example 2

As an alternative, 5-cyclopropyl-1-(3-(3-pyridyl)phenyl)benzimidazolewas prepared as described below:

-   N-(3-(3-pyridyl)phenyl)-4-bromo-2-nitroaniline. To a solution of    1-bromo-4-fluoro-3-nitrobenzene (12.9 g; 58.8 mmol) in anhydrous    N-methyl-2-pyrrolidinone (30 ml) was added 3-(3-pyridyl)aniline    (10.0 g; 58.8 mmol) and triethylamine (8.2 ml; 58.8 mmol) and the    mixture was stirred at 120° C. over night. After cooling the mixture    was poured into ice-water (300 ml) and extracted with ethyl acetate.    The extract was washed with brine, dried over magnesium sulfate and    evaporated under reduced pressure. The residue was purified by    column chromatography on silica gel using ethyl acetate as the    eluent to yield the reddish product (11.9 g; 55%).

-   N-(3-(3-pyridyl)phenyl)-2-amino-4-bromoaniline. The above product    (11.8 g; 31.9 mmol) was dissolved in a mixture of ethanol (150 ml)    and dichloromethane (50 ml) and hydrogenated at ambient pressure,    using Raney nickel as the catalyst, until the hydrogen uptake had    ceased. The mixture was filtered through filter aid and the filtrate    was evaporated to dryness to leave the desired phenylendiamine,    quantitatively.

-   5-Bromo-1-(3-(3-pyridyl)phenyl)benzimidazole. To a solution of the    above diamine (10.0 g; 29.4 mmol) in tetrahydrofurane (50 ml) was    added triethyl orthoformate (14.7 ml; 88.2 mmol) and a catalytic    amount of p-toluensulphonic acid. The mixture was stirred at reflux    for 30 min. After cooling water (300 ml) was added and the product    was filtered off, washed with water and dried. Yield 8.8 g (85.7%).

-   5-Cyclopropyl-1-(3-(3-pyridyl)phenyl)benzimidazole. The cyclopropyl    group was introduced as described in J. Am. Chem. Soc. 2001, 123,    4155-4160 from the above product and tricyclopropyl indium. The    product was purified by preparative LC-MS on an Exterra MS8 column    (27 mm×100 mm) using a mixture of A: aqueous formic acid (0.1% v/v)    and B: acetonitril as the eluent (gradient: 80% A to 60% A in 13    min.). The product elutes at 8.16 min.

Yield: 40%. Mp. 90° C.

Example 3

5-Cyclopropyl-1-(3-(1-oxy-3-pyridyl)phenyl)benzimidazole. To a solutionof 5-cyclopropyl-1-(3-(3-pyridyl)phenyl)benzimidazole (0.40 g, 1.3 mmol)in dichloromethane (20 ml) was added m-chloroperbenzoic acid (0.35 g,1.4 mmol) and the resultant mixture was stirred at room temperature for2 hours. Saturated, aqueous sodium carbonate was added and the layerswere separated. The organic layer was dried over magnesium sulphate andevaporated to dryness. The desired product precipitated from the residueupon trituration with tertbutyl methyl ether (0.27 g) Mp 169-170° C.

Example 4

N-(4-Cyclohexyl-2-nitrophenyl)acetamide. A mixture of4-cyclohexylaniline (10.0 g, 57.1 mmol) and acetic anhydride (50 ml) wasstirred at 50° C. for 1 hour. The resultant mixture was cooled in anice-bath and a solution of potassium nitrate (10.0 g, 99.0 mmol) inconc. sulphuric acid (25 ml) was added drop-wise keeping the temperatureat 15-18° C. After the addition, the mixture was poured into ice-water(400 g). The precipitate was filtered off, washed with water and dried.This crude product (12 g) contained a 1:1 mixture of mono- anddinitrated product. The desired product was isolated by columnchromatography on silica gel, using a mixture of petroleum ether andethyl acetate (9:1, v/v) as the eluent (6.5 g).

-   4-Cyclohexyl-2-nitroaniline. To a solution of the above product (3.5    g, 13.3 mmol) in dimethoxyethane (30 ml) was added aqueous sodium    hydroxide (40 ml, 1M). The resultant mixture was stirred at 40° C.    over night and was then poured into water (200 ml). The layers were    separated and the aqueous layer was extracted with diethyl ether.    The combined organic extracts were dried over magnesium sulphate and    evaporated under reduced pressure to leave the desired product,    quantitatively.

-   N-(3-Bromophenyl)-4-cyclohexyl-2-nitroaniline. A mixture of the    above product (2.1 g, 9.6 mmol), 1-bromo-3-iodobenzene (5.4 g, 19.1    mmol), potassium carbonate (1.4 g, 10 mmol) and a catalytic amount    of copper powder was stirred at 200° C. over night. The reaction    mixture was cooled to 100° C. and toluene was added. The resultant    mixture was stirred at 100° C. for 30 min and was then filtered    while hot. The filtrate was concentrated under reduced pressure and    the concentrate was eluted through silica gel with a mixture of    petroleum ether and ethyl acetate (9:1, v/v) to afford the desired    product (0.76 g) in mixture with    N-(3-iodophenyl)-4-cyclohexyl-2-nitroaniline.-   4-Cyclohexyl-N-(3-(1-imidazolyl)phenyl)-2-nitroaniline. A mixture of    the above product (0.76 g), imidazole (0.55 g, 8.1 mmol), potassium    carbonate (0.3 g, 2.2 mmol) and a catalytic amount of copper powder    was heated to 170° C. for 3 hours. The reaction mixture was cooled    to 100° C., water was added and the resultant mixture was allowed to    cool to room temperature prior to extraction with diethyl ether. The    etheral extract was dried over magnesium sulphate and evaporated    under reduced pressure. The residue was purified by column    chromatography on silica gel using ethyl acetate as the eluent to    afford the desired product (0.25 g).-   4-Cyclohexyl-N-(3-(1-pyrrolyl)phenyl)-2-nitroaniline is prepared in    a similar manner from N-(3-bromophenyl)-4-cyclohexyl-2-nitroaniline    and pyrrole.-   4-Cyclohexyl-N-(3-(1-pyrazolyl)phenyl)-2-nitroaniline is prepared in    a similar manner from N-(3-bromophenyl)-4-cyclohexyl-2-nitroaniline    and pyrazole.-   2-Amino-4-cyclohexyl-N-(3-(1-imidazolyl)phenyl)aniline. To a    solution of 4-cyclohexyl-N-(3-(1-imidazolyl)phenyl)-2-nitroaniline    (0.25 g, 0.7 mmol) in methanol (10 ml) was added a catalytic amount    of palladium (5% on activated carbon). The resultant mixture was    hydrogenated at ambient pressure until the hydrogen uptake had    ceased, whereafter it was filtered through celite. The filtrate was    evaporated under reduced pressure to afford the desired product,    quantitatively.-   2-Amino-4-cyclohexyl-N-(3-(1-pyrrolyl)phenyl)aniline is prepared    analogously from    4-cyclohexyl-N-(3-(1-pyrrolyl)phenyl)-2-nitroaniline.-   2-Amino-4-cyclohexyl-N-(3-(1-pyrazolyl)phenyl)aniline is prepared    analogously from    4-cyclohexyl-N-(3-(1-pyrazolyl)phenyl)-2-nitroaniline.-   5-Cyclohexyl-1-(3-(1-imidazolyl)phenylbenzimidazole, hydrochloride.    A solution of 2-amino-4-cyclohexyl-N-(3-(1-imidazolyl)phenyl)aniline    (0.2 g, 0.6 mmol) in formic acid (1 ml) was stirred at reflux for 4    hours. The cooled mixture was rendered alkaline by addition of    aqueous sodium hydroxide (6M) and extracted with ethyl acetate. The    organic extract was dried over magnesium sulphate, concentrated    under reduced pressure and eluted through silica gel with a mixture    of ethyl acetate and ethanol (4:1, v/v). The desired product    precipitated as the hydrochloride upon addition of etheral hydrogen    chloride to the eluate. (0.1 g) Mp 222-225° C.-   5-Cyclohexyl-1-(3-(1-pyrrolyl)phenyl)benzimidazole is prepared    analogously from    2-amino-4-cyclohexyl-N-(3-(1-pyrrolyl)phenyl)aniline.-   5-Cyclohexyl-1-(3-(1-pyrazolyl)phenyl)benzimidazole is prepared    analogously from    2-amino-4-cyclohexyl-N-(3-(1-pyrazolyl)phenyl)aniline.

Test Methods

Test Method 1

In Vitro Inhibition of ³H-flunitrazepam (³H-FNM) Binding

The GABA recognition site and the benzodiazepine modulatory unit canselectively be labelled with ³H-flunitrazepam.

Tissue Preparation

Preparations are performed at 0-4° C. unless otherwise indicated.Cerebral cortex from male Wistar rats (150-200 g) is homogenised for5-10 sec in 20 ml Tris-HCl (30 mM, pH 7.4) using an Ultra-Turraxhomogeniser. The suspension is centrifuged at 27,000×g for 15 min andthe pellet is washed three times with buffer (centrifuged at 27,000×gfor 10 min). The washed pellet is homogenized in 20 ml of buffer andincubated on a water bath (37° C.) for 30 min to remove endogenous GABAand then centrifuged for 10 min at 27,000×g. The pellet is thenhomogenized in buffer and centrifuged for 10 min at 27,000×g. The finalpellet is resuspended in 30 ml buffer and the preparation is frozen andstored at −20° C.

Assay

The membrane preparation is thawed and centrifuged at 2° C. for 10 minat 27,000×g. The pellet is washed twice with 20 ml 50 mM Tris-citrate,pH 7.1 using an Ultra-Turrax homogeniser and centrifuged for 10 min at27,000×g. The final pellet is resuspended in 50 mM Tris-citrate, pH 7.1(500 ml buffer per g of original tissue), and then used for bindingassays. Aliquots of 0.5 ml tissue are added to 25 μl of test solutionand 25 μl of ³H-FNM (1 nM, final concentration), mixed and incubated for40 min at 2° C. Non-specific binding is determined using Clonazepam (1μM, final concentration). After incubation the samples are added 5 ml ofice-cold buffer and poured directly onto Whatman GF/C glass fibrefilters under suction and immediately washed with 5 ml ice-cold buffer.The amount of radioactivity on the filters is determined by conventionalliquid scintillation counting. Specific binding is total binding minusnon-specific binding.

Results

25-75% inhibition of specific binding must be obtained, beforecalculation of an IC₅₀.

The test value will be given as IC₅₀ (the concentration (μM) of the testsubstance which inhibits the specific binding of ³H-FNM by 50%).

${lC}_{50} = {( {{{applied}\mspace{14mu}{test}\mspace{14mu}{substance}\mspace{14mu}{concentration}},{\mu\; M}} ) \times \frac{1}{( {\frac{C_{o}}{C_{x}} - 1} )}}$

where

C_(o) is specific binding in control assays, and

C_(x) is the specific binding in the test assay.

(The calculations assume normal mass-action kinetics).

1. A compound of the Formula I:

or an N-oxide thereof, or any of its stereoisomers or any mixture of itsstereoisomers, or a pharmaceutically acceptable salt thereof, wherein Rrepresents cyclopropyl; and R′ represents a 5-7-member heterocyclicring; which heterocyclic ring may optionally be subsituted one or moresubstituents independently selected from the group consisting of withhalo, hydroxy, amino, alkylamino, aminoalkyl, alkylaminoalkyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, alkoxy, alkoxyalkyl,cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, and alkynyl.2. The compound of claim 1, wherein R′ represents a heterocyclic ringselected from the group of pyridyl, thiazolyl, isoxazolyl, imidazolyl,pyrrolyl and pyrazolyl, which heterocyclic ring may optionally besubstituted with one or more halo.
 3. The compound of claim 1, which is5-Cyclopropyl-1-(3-(3-pyridyl)phenyl)benzimidazole;5-Cyclopropyl-1-(3-(2-thiazolyl)phenyl)benzimidazole;5-Cyclopropyl-1-(3-(2-fluoro-5-pyridyl)phenyl)benzimidazole;5-Cyclopropyl-1-(3-(3-isoxazolyl)phenyl)benzimidazole;5-Cyclopropyl-1-(3-(1-oxy-3-pyridyl)phenyl)benzimidazole; or an N-oxidethereof, or any of its stereoisomers or any mixture of itsstereoisomers, or a pharmaceutically acceptable salt thereof.
 4. Apharmaceutical composition, comprising a therapeutically effectiveamount of a compound of claim 1, or an N-oxide thereof, or any of itsstereoisomers or any mixture of its stereoisomers, or a pharmaceuticallyacceptable salt thereof, together with at least one pharmaceuticallyacceptable carrier, excipient or diluent.
 5. A method for treatment, oralleviation of anxiety, convulsions or sleep disorders in a livinganimal body, which method comprises the step of administering to saidliving animal body in need thereof a therapeutically effective amount ofa compound according to claim 1, or an N-oxide thereof, or any of itsstereoisomers or any mixture of its stereoisomers, or a pharmaceuticallyacceptable salt thereof.
 6. The method for the manufacture of apharmaceutical composition, comprising incorporating the compound ofFormula I as recited in claim 1 or an N-oxide thereof, or any of itsstereoisomers or any mixture of its stereoisomers, or a pharmaceuticallyacceptable salt thereof into a pharmaceutically acceptable carrierselected from the group consisting of powders, tablets, pills, capsules,cachets, suppositories, dispersible granules, solutions, suspensions andemulsions.
 7. The method according to claim 5, wherein said livinganimal body is a human.